Oral isotretinoin was effective in the prevention of skin cancer and in the treatment of a variety of disorders of keratinization (lamellar ichthyosis, Darier's disease, pityriasis rubra pilaris), and cystic acne. Oral etretinate was more effective and less toxic than isotretinoin in the treatment of the disorders of keratinization. Psychological testing revealed decreased anxiety and depression in cystic acne patients after treatment with isotretinoin. One chronic toxicity, "retinoid hyperostosis," characterized by anterior spinal ligament calcification and osteophyte formation of vertebrae, and extraspinal tendon and ligament calcification has been observed in patients treated with long-term, high-dose isotretinoin. Sixty percent of acne patients with moderate doses of isotretinoin for 9 months also developed vertebral osteophytes. Extraspinal tendon and ligament calcification also occurred commonly after chronic therapy for psoriasis and disorders of keratinization with etretinate, an aromatic retinoid. The usual sites of involvement were the ankles, pelvis and knees. Due to storage in fat, serum levels extretinate can be measured for prolonged periods (> 2 years) after discontinuation of therapy. Seven patients with xeroderma pigmentosum were entered into a cancer chemoprevention study using isotretinoin: results indicate significant partial inhibition of new tumor formation during therapy and a marked increase in new tumor formation after therapy. Long-term therapy with low-dose isotretinoin is now being used for cancer chemoprevention in these patients. The need for continuous maintenance therapy for chemoprevention of skin cancer with isotretinoin may vary with the underlying etiology (genetic or environmental) of the patient's tumors.